Composition For Improving Skin Lipid Barrier Function

ABSTRACT

The invention relates to a composition for topical application to the skin comprising effective amounts of a protease inhibitor and a cell differentiation enhancer. The composition is useful in promoting skin lipid barrier repair and maintaining the integrity of the lipid barrier. In this regard, the compositions can be used in the treatment and prevention of dry skin, and associated chrono/proto-aging conditions, in the treatment and prevention of irritation on the skin, in the treatment and prevention of UV-related damage to the skin, and in the enhancement of the retention of self-tanning.

This application is a continuation of and claims benefit from U.S. Ser.No. 09/554984, filed Apr. 4, 2000, which is the filing date ofInternational application US00/08871.

FIELD OF THE INVENTION

The invention relates to cosmetic and pharmaceutical compositions. Morespecifically, the invention relates to topical compositions that areuseful in enhancing the function of the skin's natural lipid barrier.

BACKGROUND OF THE INVENTION

Skin is typically characterized as consisting of three distinct layers,namely the stratum corneum, the epidermis and the dermis. The stratumcorneum, the outermost layer, is made up of keratinized, cells,surrounded by intercellular space filled with lipids. The stratumcorneum provides a substantial physical barrier to penetration of mostsubstances to the lower layers of the skin. In addition to preventingtransport of substances to the other skin layers, however, this harrieralso aids in prevention of water loss from the skin. Both functions areprimarily attributable to the presence of the lipids in the stratumcorneum.

There are two sources of the skin surface lipids making up thisimportant barrier; sebaceous glands and the epidermis. The lipids are adiverse group of compounds, comprising triglycerides, diglycerides,ceramides, free fatty acids, wax esters, cholesterol and cholesterolesters, and squalene. The quantity and composition of the skin surfacelipids differ from place to place on the body, and may to some extent berelated, to the number of sebaceous glands in a given area of the skin.The condition of the skin surface lipids may also he affected by anessential fatty acid deficiency. Additionally, the lipid barrier iseasily diminished by exposure to harsh detergents or soaps, it isapparent, then, that the quality of the skin lipid barrier can varywidely, depending on a number of different factors, and therefore, maynot always be adequate to perform its protective function optimally.

As an attempt to compensate for what may be a less than adequate lipidbarrier, cosmetic compositions frequently incorporate components whichcompensate for water loss. Examples of such materials are hygroscopichumectants, e.g., urea or propylene glycol, which hold water on theskin; or emollients, e.g., oleyl alcohol or caprylic/caprictriglycerides. Certain cosmetic components may be occlusive skinconditioners, which are used to provide an “artificial” barrier; suchcompounds are frequently lipids which remain on the skin surface, andinclude various hydrogenated oils, waxes and butters. Although many ofthese products provide an effective means of steaming water loss fromthe skin, they do have to be reapplied frequently to maintain theeffect, and do not generally constitute a natural-occurring component ofthe stratum corneum, potentially giving rise to an unnatural, greasyfeel to the skin. In addition, various pharmaceutical or cosmetic activeagents are also frequently used to treat the symptoms of dryskin-associated conditions; however, in many cases, particularly withpharmaceutical agents, the treatments themselves may cause undesirableside effects in the individual being treated, while ultimately resultingin no actual repair of the lipid barrier.

The most desirable situation, from a functional point of view, is tofind a way to enhance the skin's own ability to maintain and/or repairthe strength of its barrier, so that the protective barrier formed iscompletely natural. It has now been discovered that a combination ofspecific skin active agents results in an unexpected increase in thestrength of the natural barrier, by stimulating the production andmaintenance of the barrier's naturally occurring components. There isthus provided a new type of cosmetic or pharmaceutical composition whichfunctions by enhancing the skin's own functions, resulting in a morenatural means of preventing dry skin and other undesirable results of adeficient lipid, barrier.

SUMMARY OF THE INVENTION

The invention relates to cosmetic and pharmaceutical compositionscomprising lipid barrier-enhancing effective amounts of at least oneprotease inhibitor and at least one cellular differentiation enhancer.The composition can also comprise, in a preferred embodiment, effectiveamounts of a sterol sulfate, an at least one naturally occurring skin,lipid component. The composition of the invention can be used in amethod for strengthening the natural lipid barrier of the skin, as wellas other methods of skin treatment that are made possible by thestrengthening of the barrier.

DETAILED DESCRIPTION OF THE INVENTION

The combined actives of the composition of the invention have been foundto be highly effective in stimulating the repair of a damaged lipidbarrier, and therefore, are shown to be useful as well in maintenance ofa normal and healthy lipid barrier. For the purposes of the presentinvention and claims, these abilities will be referred to asstrengthening the lipid barrier. The compositions of the invention canstrengthen the lipid barrier at least about 40%, relative to a placebocontrol, as measured by a reduction of transepidermal water loss (TEWL)after a barrier challenge, a standard measurement of barrier function.Preferably, the compositions are capable of reducing TEWL at least about50%, more preferably at least about 60%, and most preferably at leastabout 70%. The invention incorporates as essential elements a proteaseinhibitor and a cellular differentiation enhancer. Protease inhibitorsare compounds, usually naturally occurring, which inhibit the action ofproteases in the skin. Skin proteases also occur, naturally, and, amongother effects, are involved in the breaking down of the collagen andelastin that is required to maintain the healthy appearance of skin, inthe present case, the protease inhibitors used in the invention arethought to act by preventing the breakage of the desmosome bond betweencorneocytes at the skin surface, thereby keeping the outer layer of skincells intact, in essence delaying desquamation. This skin layer providesa barrier to water loss, and the enhanced retention of the barrier bythe delay of desquamation provides reinforces this barrier to the lossof water further. A variety of protease inhibitors are known. Examplesof useful protease inhibitors include, but are not limited to,triterpenoid-containing extracts and refined compounds, for example,,white birch bark extract, silver birch bark extract, Boswellia extract,bearberry extract, Centella asiatica extract, or Pygeum (Prunus)africanum extract and individual protease inhibitor compounds that mayfoe present in these extracts, including betulinol (betulin), foetulinicacid, boswellic acid, ursolic acid, oleanolic acid, oleanol,asiaticoside, asiatic acid, and madagassic acid; phenolic-containingextracts, such as green tea extracts and apple extracts, and compoundscontained therein, such as EGCG, EGG, cacechins, phenylpropanoids, andphloretin; protein-based extracts, such as soy protein, or egg proteaseinhibitors, or cholesterol sulfate and phytosterol sulfates. Preferredprotease inhibitors are triterpenoids, particularly boswellic acid,betulinol, and betulinic acid, or extracts containing same insubstantial quantities.

It will be recognized from the foregoing that either an extract or theindividual protease inhibitor can be used, and that the individualprotease inhibitors can also be found in other types of extracts. Theamount of active material used will vary depending upon the whether anextract or isolated compound is used, the concentration of activematerial in a given extract, and the known potency of the activematerial. However, the concentration of active protease inhibitor in thefinal product should generally be between about 0.001 to about 10%,preferably about 0.05 to about 5%, more preferably about 0.1 to about1%, by weight of the total composition.

The second component is a cellular differentiation enhancer. Suchcompounds act in the present invention to increase the ability of therelevant epidermal cells to synthesize the lipids that constitute theprimary component of the barrier. The epidermal cells that producelipids do not do so during their entire life cycle, however, but do soonly at the point of differentiation. If this differentiation is delayedto the point, at which the epidermal cells reach their terminal point inmigration, to the skin surface, the production of lipids is concurrentlydelayed, and therefore, their effect, if any, is diminished. Thedifferentiation enhancers used in the invention stimulate the earlierproduction of lipids from epidermal cells, thereby increasing the lengthof time, over which the lipids are being produced, and presumablyconcurrently increasing the lipid content of the barrier. Several typesof cellular differentiation inhibitors, are known, and these include,but are not limited to sclareolide, forskolin, 7-dehydrocholesterol, andVitamin D3analogs. The differentiation enhancer also will be used inamount consistent with its known activity, 0.001 to 10%, preferablyabout 0.0025 to about 5%, more preferably about 0.05 to about 1%, byweight of the total composition.

The combination of the protease inhibitor and the differentiationenhancer is shown to have a strong effect on barrier repair whencompared with control vehicles and with other compounds commonly used inskin enhancement. Specifically, on skin that had been challenged withtape stripping, it was found that combination of these two componentsexhibits about a 50% increase in barrier repair, as measurable bytransepidermal water loss, in comparison with the placebo, after aperiod of three days. Thus, this combination on its own is shown to beable to increase barrier function substantially.

Although the noted combination is highly effective on its own, it hasbeen further shown that the combination achieves even furtherenhancement of barrier function by its combination with, certain otherskin enhancement compounds. More specifically, the combination with oneor more of certain specific skin enhancers. In a preferred embodiment,the barrier repair combination is further combined with cholesterolsulfate, which in the present specification and claims is intended torefer to the corresponding plant-derived material, phytosterol sulfate.Cholesterol sulfate, as described in Applicants' copending applicationSer. No. 09/246,607, incorporated herein by reference, also has aneffect on the skin, by increasing the cohesion of the stratum corneum.Thus, its combination with the protease inhibitor/differentiationenhancer even further strengthens the ability of the compositionmaintain the integrity of the stratum corneum. The amount of cholesterolsulfate employed is preferably about 0.05 to about 10%, preferably fromabout 0.5 to about 5%, most preferably about 1 to about 3%, by weight ofthe total composition.

In all formulations in which cholesterol sulfate is employed, and in aparticularly preferred embodiment, it is preferred that the compositionalso contain other components of the naturally occurring lipid barrier.In a particularly preferred embodiment, the cholesterol sulfate iscombined with at least, one of each of fatty acids, ceramides, and asterol, preferably cholesterol or phytosterol. Fatty acids may be up to24 carbon atoms in length. Examples of preferred fatty acids includebutyric acid, caproic acid, octanoic acid, decanoic acid, dodecanoicacid, tetradecanoic acid, palmitic acid, stearic acid, linoleic acid andoleic acid. Particularly preferred are fatty acids with a C₁₂ to C₂₀chain length.

The ceramides to be employed in the compositions of the invention aresphingolipids, having a sphingesine or related molecule backbone withfatty acids or ω-esterified fatty acids linked to an amino group on thesphingosine, and in some cases, with saccharide moieties linked to theterminal hydroxyl of the sphingesine. In particular, the compositionsmay contain ω-esterified ceramides or acylceramides, cereforosides,ω-esterified cerebrosides, or acylglycosyl sphingolipids. Particularlypreferred types of ceramides for the present compositions are ceramideIII and cerehrosides.

In those compositions in which cholesterol sulfate is combined withthese lipids, the lipid components each can be used in an amount of fromabout 0.05 to 10%, preferably 0.5 to about 5%, most preferably about 1to about 3%, all by weight of the total composition. In a particularlypreferred embodiment, the cholesterol sulfate and the lipid componentsare present in substantially equal amounts in the composition. It willbe understood from the foregoing that the lipid component need not bepure lipid, but rather may be natural extracts containing one or moredesirable lipids, and used in amounts consistent with attaining theconcentrations recommended above.

The effect of the present compositions in effecting barrier repair ormaintaining the integrity of the skin's outer layer can be applied to anumber of different uses. For example, the compositions can be used totreat any condition in which a deficient or faulty barrier is a factor.In this regard, the compositions can foe used to improve the long termmoisture retention of the skin, or in prevention or treatment of dryskin conditions generally, or specific dry skin conditions, such asresult from regular exposure to detergents, soaps and hot water;seasonal exposure to harsh weather conditions, e.g., cold, wind and/orsun; occupational exposure to harsh chemicals or other drying ordamaging agents; or pathological conditions such as eczematousdermatides, psoriasis, ichthyoses, xerosis and the like. It is alsowell-known that dry skin is commonly associated with aging (bothintrinsic and photoaging), and the compositions can be used inprevention of further damage to aging skin, or treatment and/or reversalof already present damage, including the appearance of fine lines andwrinkles, which, are frequently associated with dry skin and thethinning of the stratum corneum that occurs with age. The compositionscan also be used in the treatment of a defective skin barrier, such, asoccurs on the soles of the feet, and palms of the hands, where thestratum corneum is very thick, but the lipid barrier is poor. Inaddition, defective skin barriers frequently occur in association withburns, wounds, blisters, stasis ulcers and bedsores; such injuries canbe expected to benefit from application of the compositions.

In further use of the compositions of the invention is in reduction ofthe skin's response to irritants and sensitizers. A significantpercentage of the population considers itself to have sensitive skin, inthat they perceive a frequent, stinging or painful response to variouselements to which the skin may be exposed, be it through makeup or skincare products, environmental stimuli such as smoke or pollution, oroccupational exposure to chemicals. In addition, even normal skin canhave a reaction to exposure to known irritants, such as acids. As it iswell known that the stratum corneum and lipids constitute the first lineof defense against irritants, by providing a physical barrier topermeability of such materials to the lower skin layers, the applicationof the compositions of the invention, by increasing the integrity of thebarrier, can reduce the reactivity of the skin of both normal andsensitive individuals to irritants and sensitizers, in one embodiment,for example, the compositions can be used to reduce the reaction of theskin to the irritation caused by therapeutic acids such as alpha andbeta hydroxy acids, retinoic acid, and the like, or to reduce theirritation caused by insect bites or stings, or alleviate the irritationexperienced with contact dermatitis.

The increased cohesion of the stratum corneum brought about by thecompositions of the invention also provides other benefits. The stratumcorneum represents an important physical barrier between the environmentand the deeper skin layers as well as the internal organs. The presenceof this thicker layer thus will provide a greater level of protectionthan is possible with weaker barrier. Perhaps the most important aspectof this effect is the enhanced self-protection from UV rays. The thickerstratum corneum means an increase in the Minimal Erythemal Dose of UVwhich will result in sunburn or more serious skin damage. In connectionwith this aspect of the invention, the components of the invention mayfoe beneficially combined with one or more sunscreens for an enhanced UVprotective composition which provides both short- and long-termprotection. Thus, the invention provides sunscreen compositionscomprising effective amounts of the components of the composition of theinvention, and one or more sunscreens. Examples of useful sunscreensinclude, but are not limited to, inorganic sunscreens such as titaniumdioxide, sine oxide, and iron oxide; and organic sunscreens, such ascamphor derivatives, cinnamates, salicylates, benaophenones, triazines,PABA derivatives, diphenylacrylate derivatives, and dibenzoylmethanederivatives. In such sunscreen compositions, the components of theinvention are present in the amounts described above, and the respectivesunscreens are present in the amounts normally used for UV protection.

An additional use of the compositions of the invention is in theenhancement and prolongation of self-tanning products. One of therecognised limitations of self-tanners, which are normally based ondihydroxyacetone (DHA) as the active component, is that the tan on theskin lasts only as long as the skin cells receiving the DHA remain inplace. In the normal course of events, then, a self-applied tan usuallylasts no more than 5 days, i.e., for as long as it takes for the stratumcorneum layer to which the DHA was applied to fully turn over. When thecompositions of the invention are combined with DHA, or any otherself-tanning agent, in a typical self-tanning formulation, however, therate of turnover of the stratum corneum to which the composition isapplied is slowed down, thereby permitting a longer rate of retention ofthe “tanned” cells, and thus prolonging the length of time the tanremains visible on the skin. Thus, the invention provides a self-tanningcomposition comprising a protease inhibitor, a cell-differentiationenhancer, and an effective amount of a self-tanning agent, optionallycontaining cholesterol sulfate and the lipid component. In a preferredembodiment, the self-tanner is DHA, which is usually applied in anamount of from about 2.5 to about 10% by weight of the formulation. Theself-tanner may also be imidazole, preferably in combination with. DHA,in an amount of about 1-10%, preferably about 1.5-7.5%.

The compositions of the invention are employed in a manner appropriateto the intended final use of the product. For example, in the treatmentof occasional dry skin due to exposure to weather or other temporaryconditions, or in the treatment of occasional skin irritation, thecompositions can he used on an as-needed basis until the condition isrelieved. When being used to treat a more permanent condition, forexample, a condition associated with a defective or deficient lipidbarrier, particularly sensitive skin, dry skin associated with any typeof aging, or the wrinkling or fine lines associated with a thinning ofthe stratum corneum with aging, the composition, is preferably appliedchronically, to prevent recurrence of the condition. For this purpose,it is suggested as an example that topical application of thecomposition, in an amount of from about 0.1 mg/cm² to 2 mg/cm² of skin,be performed, from about once per week to about 4 or 5 times daily,preferably from about 3 times a week to about 3 times daily, mostpreferably about once or twice per day. By “chronic” application, it ismeant, herein that the period of topical application may be over thelifetime of the user, preferably for a period of at least about onemonth, more preferably from about three months to about twenty years,more preferably from about six months to about ten years, morepreferably still from about one year to about five years, therebyresulting in the treatment or prevention of the condition in question.

When the composition is used in conjunction with a sunscreen, it isapplied in the same amounts as specified above, on an as-needed basis,to mitigate the effects of exposure to the sun. When used in combinationwith a self-tanner, the composition is also applied in similar amounts,on the portion of the skin to be tanned, with repetition, again, on anas-needed basis.

The invention is further illustrated by the following non-limitingexamples:

EXAMPLES Example 1

A study is conducted to determine the efficacy of certain compositionsin enhancing repair of the lipid barrier. Female volunteers with normalskin, who are in good general health, free of any dermatologicaldisorders, participate in the study. Their skin barrier is challenged bytape stripping according to the procedure outlined below. After theirevaluation, the subjects receive a treatment every day on the right sideof their face. They are also given the product containing the actives touse once every night for three nights, on the right side of the faceonly, the left side being the untreated control side. A separate groupis given a placebo, without actives, as treatment product.

To challenge the barrier, the subjects are acclimated in anenvironmental room at 40% relative humidity and 70° C. for 15-20minutes.A 5 cm by 1 cm area is marked on the lower right cheek near the jaw lineand initial water evaporation measurements are taken in three separatespots approximately 1 cm apart in a row. Five cm of cello-tape is placedon the skin in the outlined area, starting from the top of the cheek andafter one firm stroke in each direction it is removed by gently pullingin a downward direction parallel to the skin. The procedure is repeatedand water evaporation is measured after every five strips until thebarrier is disrupted as indicated by a minimum of 18 g/sq.m hr on one ofthe three spots. Both sides of the face are stripped in the same way.The subjects returned for TEWL evaluation 1, 2 and 3 days after tapestripping of the skin to monitor the repair,

Barrier repair is evaluated by first challenging the skin as describedabove. One side is product-treated 2 times a day, and the other is theuntreated control. Repair is measured in the increase in the recovery ofthe skin on the stripped and treated site compared to the strippeduntreated site. From this, total repair is calculated over three days bycalculating the change in the area parameter, The smaller the area, thetaster the repair.

Treatment products are (1) a composition containing 0.1% sclareolide and0.2% white birch extract; (2) a composition containing 0.1% sclareolideand 0.2% boswellic acid; (3) a composition containing 0.2% each ofphytocohesine (phytosterol sulfate), ceramides (wheat-derivedceramides), boswellic acid, cholesterol, and linoleic acid, and 0.1%sclareolide. The results obtained indicate for composition (1), barrierrepair is 50% over placebo; for composition (2), repair is 59% overplacebo, and composition (3) is shows barrier repair at 78% over theplacebo, each composition therefore showing substantial efficacy inbarrier repair.

1. A composition for topical application to the skin comprising from0.001 to 10% of at least one protease inhibitor selected from the groupconsisting of white birch extract, silver birch extract, Boswelliaextract, bearberry extract, Centella asiatica extract, Pygeum (Prunus)africanum extract, betulinol, betulinic acid, boswellic acid, ursolicacid, oleanolic acid, oleanol, asiaticoside, asiatic acid, madagassicacid, green tea extract, apple extracts, EGCG, ECG, catechins,phenylpropanoids, phloretin, soy protein, egg protease inhibitors,cholesterol sulfate, phytosterol sulfate, and combinations thereof, andfrom 0.001 to 10% of at least one cell differentiation enhancer selectedfrom the group consisting of forskolin, sclareolide,7-dehydrocholesterol, and Vitamin D3 analogs.
 2. The composition ofclaim 1 in which the cell differentiation enhancer is sclareolide. 3.The composition of claim 2 in which the protease inhibitor is selectedfrom the group consisting of white birch extract, betulinol, betulinicacid, Boswellia extract, boswellic acid, and combinations thereof. 4.The composition of claim 2 in which the protease inhibitor is whitebirch extract, betulinol, or boswellic acid.
 5. The composition of claim1 in which the protease inhibitor is cholesterol sulfate.
 6. Thecomposition of claim 5 which also contains at least one fatty acid, atleast one ceramide, and at least one sterol.
 7. The composition of claim6 in which the fatty acid is a C12-C20 fatty acid.
 8. The composition ofclaim 6 containing about 0.05 to 10% of each of cholesterol sulfate,fatty acid, ceramide, and sterol.
 9. The composition of claim 1 whichfurther comprises at least one sunscreen.
 10. The composition of claim 1which further comprises a self tanning agent.
 11. The composition ofclaim 10 in which the self tanning agent is dihydroxyacetone.
 12. Thecomposition of claim 1 comprising about 0.1 to 1% of the proteaseinhibitor and about 0.05 to 1% of the cell differentiation enhancer. 13.A method for treatment or prevention of dry skin which comprisesapplying to the skin a composition according to claim
 1. 14. A methodfor reducing or preventing skin's response to irritants or sensitizerscomprising applying to the skin a composition of claim
 1. 15. A methodfor protecting skin against effects of exposure to UV radiationcomprising applying to the skin a composition of claim
 1. 16. A methodfor protecting skin against effects of exposure to UV radiationcomprising applying to the skin a composition of claim
 9. 17. A methodfor tanning the skin without exposure to the sun comprising applying tothe skin a composition according to claim 10.